1. Field of the Invention
The present invention is in the area of therapeutic devices and methods for treating diseases and conditions of the human eye, and related more particularly to systems for supplying oxygen for treatment.
2. Discussion of the State of the Art
Importance of oxygen for the human eye is well understood, and Retinal hypoxia—a reduction in the delivery of oxygen to the retina—has been implicated as an underlying cause of a number of eye (retinovascular) diseases such as diabetic retinopathy, diabetic macular edema, age-related macular degeneration, sickle cell disease, retinopathy of prematurity, familial exudative retinopathy, retinal vascular occlusions, ocular ischemic syndrome, and other related conditions. As such diseases progress, there develops some combination of relative impermeability of normally permeable tissues to oxygen diffusion or a closure of retinal capillaries, leading to hypoxia. The hypoxia, in turn, stimulates the production of vascular endothelial growth factor (VEGF) leading to subretinal, intraretinal, or extraretinal neovascularization. VEGF also stimulates vascular permeability and leakage of both normal and new vessels leading to retinal edema and hemorrhage. Oxygen has been shown to be beneficial to treat these types of retinopathy.
Even though the value of oxygen to the human eye has been well-known, as discussed above, oxygen as an intraocular therapeutic agent to prevent and treat eye disease has not been routinely used because it has not been possible to sustainably deliver oxygen to the target tissues in adequate quantities into the eye to meet metabolic requirements for effective management and treatment of these and other ocular diseases.
The supply of oxygen to the retina is believed by the inventor to be pertinent to diseases such as macular degeneration and diabetic retinopathy. Under normal healthy conditions oxygen is delivered to the retina via a dual blood supply, a system called the choroid supplying the outer part of the retina, which is not heavily regulated, and a separate inner retinal vascular system that is highly influenced by metabolic feedback from the tissue within the retina, so as to maintain relatively constant oxygen supply.
Oxygen may play an important role in therapeutic treatment of eye diseases. In a recent study at Johns Hopkins (9 eyes were measured), patients with chronic Diabetic Macular Edema (DME) received 4 L/min of inspired oxygen by nasal cannula for 3 months. After 3 months of oxygen therapy, nine of nine eyes with DME at baseline showed a reduction in thickness of the center of the macula. Foveal thickness (FTH) above the normal range was reduced by an average of 43.5% (range, 14%-100%), excess foveolar thickness (CEN) was reduced by an average of 42.1% (range, 13%-100%), and excess macular volume was reduced by an average of 54% (range, 35%-100%), P=0.0077. Three eyes showed improvement in Visual Acuity by at least 2 lines, one by slightly less than 2 lines, and five eyes showed no change. Three months after discontinuation of oxygen, five of the nine eyes showed increased thickening of the macula compared with when oxygen was discontinued. Researchers concluded supplemental oxygen may decrease macular thickness due to DME, suggesting that retinal hypoxia is involved in the development and maintenance of DME. The present invention is intended to treat eye diseases.
An example of such a disease is diabetic retinopathy (damage to the retina) which is caused by complications of diabetes mellitus and can eventually lead to blindness. Diabetic retinopathy affects up to 80% of all diabetics who have had diabetes for 15 years or more Despite these intimidating statistics, research indicates that at least 90% of these new cases could be reduced with proper and vigilant treatment.
In diabetic retinopathy, as blood vessels become blocked and oxygen deprivation begins, excess growth factors start to be released to promote the growth of new blood vessels, in a process called ‘neovascularization’ in the art. Among these various growth factors, the one termed VEGF, introduced above, is found in the endothelial cells lining these blood vessels. Retinal blood vessels have three times as many receptors for VEGF as vessels elsewhere, and oxygen deficit dramatically raises VEGF levels. VEGF is believed to play a major role in stimulating neovascularization, and also in vascular leakage in the eye. Other treatments such as laser treatments that are used to treat proliferative diabetic retinopathy work in part by lowering levels of growth factors like VEGF. Antibodies and other inhibitors of VEGF are also beginning to appear in research designed to stop the growth of cancers, and some of these are being used to treat neovascular proliferation, both choroidal and inner retinal. Therapies used to treat macular degeneration and diabetic macular edema attempt to prevent VEGF over-expression or block its pathological effects in the retina. Blockage of capillaries is found in background retinopathy, but a more serious form of blockage to blood vessels occurs in preproliferative and proliferative retinopathy. Capillary drop-out impairs the delivery of oxygen and other nutrients that are required to maintain cell health. Oxygen deficit in turn triggers cell damage and release of growth factors. Although there are therapeutics to reduce or inhibit the effect of VEGF, there are no known therapeutic inventions to improve the supply of oxygen to the retina and therefore stop the trigger release of growth factors which play a major role in causation of choroidal and inner retinal neovascularization.
Retinal oxygen demand under normal conditions is very high (even higher than for the brain) and may be affected by different conditions. The relative contribution of the blood vessels of the inner retinal vasculature and those of the choroid—a layer of vascular tissue external to the retina—to the oxygenation of the retina, in health and disease, is not sufficiently understood. Human retinal oxygen consumption has been difficult to measure because any anesthesia used for in vivo measurements reduces the blood flow to the eye and the invasive nature of the measurement procedure prohibits the amount of human data that can be collected.
It is understood from oxygen microelectrode studies in animals with circulatory patterns similar to those of humans, that the inner and outer halves of the retina are different domains in terms of oxygen. Failure of inner retinal circulation (ischemia) leads to tissue hypoxia that underlies vasoproliferation in diabetic retinopathy, retinopathy of pre maturity, and the other inner retinovascular diseases.
In the macula, photoreceptors sit on a layer of pigment cells, called the retinal pigment epithelium, (RPE). These very active photoreceptors must be continuously supplied by new light-sensitive material. Used light-sensitive material is continuously absorbed by the pigment epithelium and recycled to be re-used again. This process requires oxygen and other nutrients supplied by the fine blood vessels of the choroid (choriocapillaris). Thickening of the outer RPE basement membrane, the primary pathophysiologic finding in macular degeneration, leads to diminished ability to deliver oxygen to the macular region of the retina. When the renewal process of the photoreceptors fails, the photoreceptors die and so also does the pigment epithelium. This causes a dry form of macular degeneration. Distressed photoreceptors and pigment epithelium release VEGF because they need more oxygen. As a response, the choriocapillaris attempts to make new vessels that intend to supply more oxygen to the photoreceptors (choroidal neovascularization). However, the new vessels are disorderly and have defective walls that tend to leak and bleed, damaging the macula further. This is called the wet form of macular degeneration. This, in turn, leads to exudative macular detachment and damaged photoreceptors, the main findings of age-related macular degeneration.
Choroidal blood flow is not regulated metabolically, so systemic hypoxia and elevated intraocular pressure both lead to decreases in choroidal PO2 (the partial pressure of oxygen) and photoreceptor oxygen consumption. The same lack of regulation allows choroidal PO2 to increase dramatically during hyperoxia, offering a potential for systemic oxygen to be used therapeutically in retinal vascular occlusive diseases and retinal detachment. However, to the knowledge of the inventor, there are no effective means presently available for delivering oxygen inside the eye to the retina. What is clearly needed therefore, are reliable and sustainable apparatus and methods for delivering oxygen inside the eye, particularly to the retina, for treatment of eye conditions and diseases.